Haematology: Introduction to Leukaemias Flashcards
What is leukaemia?
- A group of malignant disorders of haematopoietic stem cells characteristically associated with an increased number of white cells in bone marrow or/and peripheral blood
Name the 3 types of haematopoietic lineage and state the type of blood cell/s each lineage produces
- Erythroid lineage - produces erythrocytes
- Lymphoid lineage - produces B and T lymphocytes
- Myeloid lineage - produces all other leukocytes, e.g. neuyrophils, macrophages etc.
What are the 3 main cell types involved in haematopoiesis?
- Haematopoietic stem cells (HSCs)
- Progenitor cells
- Mature cells
What are some basic characteristics of haematopoietic stem cells?
- Pluripotent - can give rise to cells of every blood lineage
- Self maintaining - a stem cell can divide to produce more stem cells
What are some basic characteristics of progenitor cells?
- Can divide to produce many mature cells but can’t divide indefinitely
- Eventually differentiate and become mature cells
There are 2 different types of progenitor cells, what are they?
- Undifferentiated (multipotent) progenitor cells
- Committed (unipotent) progenitor cells
What differences are there in characteristics between the undifferentiated and committed progenitor cells?
- With the undifferentiated progenitor cells you can’t tell the difference between them morphologically because they don’t show the characteristics of mature cells.
- Committed prognitor cells are already committed as to what mature cells they’ll become and so are morphologically different
- Undifferentiated progenitor cells also have ability to produce more than one type of blood cell while committed progenitor cells can only produce one type
Explain what is meant when it is said that leukaemia is a “clonal disease”
- This means that all the malignant cells derive from a single mutant stem cell
What are some of the common symptoms of most types of leukaemia?
- Abnormal bruising (most common symptom)
- Repeating abnormal infection
- Sometimes anaemia
Name of the techniques used to diganose which subtype of leukaemia a person has/what treatments can be used to combat it?
- Next generation sequencing - can construct molecular profile of cancerous cells
- Fluorescence in situ hybridisation (FISH) - used to detect chromosmal abnormalities
- Immunophenotyping
- Cytomorphology
- Flow cytometry
What are some of the predisposing factors than can cause leukaemia?
- Genetic factors
- Environmental factors
- Lifestyle-related risk factors
- Uncertain/controversial factors
Is Leukaemia a hereditary disorder?
- Leukaemia usually not hereditary
- There are some cases of Chronic Lymphocytic Leukaemia (CLL) where this is the case
There are a couple of rare genetic dseases that may predispose to leukaemia. What are these genetic disorders?
- Fanconi’s anaemia
- Down’s syndrome
What are some specific genetic risk factors that can lead to the development of leukaemia?
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Gene mutations resulting in activation of oncogenes and/or inactivation of tumour suppressor genes
- Genes mutated can be common to other cancers, e.g. TP53, or specific to Leukaemia
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Chromosome aberrations:
- Translocations (e.g. BCR-ABL in CML).
- Numerical disorders (e.g. trisomy 21-Downs syndrome)
- Inherited immune system problems (e.g. Ataxia-telangiectasia)
What are some specific environmental risk factors that can lead to the development of leukaemia?
-
Radiation exposure
- Acute radiation accidents
-
Exposure to chemicals and chemoterapy
- Cancer chemotherapy with alkylating agents (e.g. Busulphan)
- Industrial exposure to benzene
-
Immune system suppression
- e.g. After organ transplant
What are some specific lifestyle-related risk factors that can lead to the development of leukaemia?
- Smoking
- Drinking
- Excessive exposure to sun
- Being overweight
What are some of the uncertain/controversial factors that may cause Leukaemia?
- Infections in early life
- Parent’s smoking history
- Foetal exposure to hormones
What specific cells are affected in acute leukaemia?
- Myoblasts
- Lymphoblasts
What is chronic Leukaemia?
- Differentiated leukaemia characterised by uncontrolled clonal accumulation of mature white blood cells (unipotent progenitors)
Explain why there’s a large number of blast cells within the blood and bone marrow in acute leukaemia
- In acute leukaemia blast cells proliferate to form a blast cell pool
- However, the blast cells get arrested within the pool so are unable to form mature cells
- Because mature cells are unable to form, the blast cell pool becomes extremely large
What are some of the main symptoms of acute leukaemia?
- Thrombocytopenia (low platelet count) - this causes purpura (bruising), epistaxis (nosebleed) and bleeding from gums.
- Neutropenia (low neutrophil count) - this causes recurrent infections and fever.
- Anaemia - this causes weakness, tiredness, shortness of breath.
What are some characteristics of chronic lymphocytic leukaemia?
- Prevalence - 3,800 new cases diagnosed in UK every year, avergae diagnosis age is 70
- Origin - Cancer of mature (clonal) lymphocytes, large amount present in blood/bone marrow
- Symptoms - Recurrent infections due to neutropenia, and suppression of normal lymphocyte function, anaemia, thrombocytopenia, lymph node enlargement and hepatosplenomegaly.
- Treatment - Regular chemotherapy
- Outcome - 5 year event-free survival rate of 83%, many patients survive more than 12 years
95% of chronic myeloid leukaemia patients have the philadelphia chromosome. What is the philadelphia chromosome?
- The short and defective chromosome formed as a result of the chromosomal translocation between the long arm of chromosome 9, which contains the ABL gene and the long arm of chromosome 22, which contains the BCR gene.
What occurs as a result of the chromosomal translocation that forms the philadelphia chromosome?
- The BCR and ABL genes fuse to form the BCR-ABL 1 fusion oncgene
- This results in the promoter for the BCR gene regulating the ABL gene as well
- The BCR-ABL 1 fusion gene produces the BCR-ABL protein which has constitutive (unregulated) protein tyrosine kinase activity
What are the effects of the unregulated protein tyrosine kinase activity of the BCR-ABL protein?
- Proliferation of progenitor cells in the absence of growth factors
- Decreased apoptosis
- Decreased adhesion to bone marrow stroma
Explain how fluoresence in situ hybridisation (FISH) is used to detect the presence of the philadelphia chromosome (BCR-ABL gene fusion)?
- Fluorescent probes are used that’ll bind to either the BCR gene or the ABL gene
- If you see a combination of the 2 colours used to fluoresecently label the probes then it confirms the presence of BCR-ABL gene fusion
Explain the mechanism of action of the targeted therapy imatinib
- imatinib is a smll molecule inhibitor that inhibits the BCR-ABL oncoprotein
- It does this by preventing ATP from binding to the BCR-ABL oncoprotein
- This results in the chronic myeloid leukaemia cells undergoing apoptosis
